There are about 1.6 million people living with HIV/AIDS in North America while 33 million people suffer from the same disease worldwide. The HIV/AIDS epidemic is driven by a rapidly replicating retrovirus that undergoes multiple mutations to current therapeutics and as such, it is extremely challenging to treat successfully. For millions of patients whose viral strain is resistant to available HIV therapies, the consequences can be fatal. One option currently available for these patients is to use a combination of medications that leads to various side effects. Although progress has been made in the global fight against HIV/AIDS, the epidemic continues to devastate the US with 56,300 new HIV infections each year and the international community with even more. There is an unmet need to discover and develop new HIV therapeutics that can successfully counter the HIV's drug resistances. New validated targets and novel therapeutics need to be identified and developed for this purpose. (Cohen, J. Science, 2010, 330, 1301).
An intensive effort over the past twenty years has led to the development of several classes of effective antiviral drugs that have significantly improved patient survival (Simon et al., Lancet, 2006, 368, 489-584). However, current drug regimens control, but not eradicate HIV-1 in the infected patient, necessitating a long-term treatment. This unavoidably leads to problems of drug tolerance and resistance limiting treatment options for many patients. The seriousness of drug resistance has driven researchers to identify novel drugs that target previously untested biochemical steps in the HIV-1 replication cycle (Adamson et al., Drug Discov. Today, 2008, 13, 424-432; Greene et al., Antiviral Res. 2008, 80, 251-265). Current invention is exploiting one such critical step in HIV replication for the design and development of new therapeutics.
All retroviruses use a particular host cell transfer RNA (tRNA) as the primer for reverse transcription (RT) of their single-stranded RNA genomes into double-stranded DNA. HIV is a lentivirus and as such, uses the human tRNA3Lys (htRNA3Lys, also known as tRNALys3 or tRNALys3UUU where the UUU is the tRNA's anticodon or tRNALys3SUU where the S refers to the natural modified nucleoside in the anticodon, 5-methoxycarbonylmethyl-2-thiouridine) species as the primer of RT (Marquet et al., Biochimie. 1995, 77, 113-124; Arts et al., PNAS 1996, 93, 10063-10068; Kleiman et al., FEBS Lett. 2010, 584, 359-365.). Mutations at the primer binding site (PBS) are not sufficient to produce a lasting substitution of another human tRNA as the primer (Moore-Rigdon, K. et al., Retrovirology 2005, 2, 21). Prolonged culturing of the mutants results in reversion to htRNA3Lys as the primer for RT (Id.).
The majority of clinically approved drugs target the viral enzymes reverse transcriptase (RT) and protease (PR). RT inhibitors fall into one of two classes based on their mode of action: the nucleoside-analog RT inhibitors (NRTIs) are incorporated into the growing DNA strand and serve as chain terminators; and the non-nucleoside RT inhibitors (NNRTIs) bind RT and induce conformational changes that inhibit RT polymerization activity (Jochmans, D. Virus Res. 2008, 134, 171-185). A better understanding of the viral life cycle and biochemistry has led to viral protease inhibitors (PIs) (Schultz et al., Virus Res. 2008, 134, 86-103). PIs competitively inhibit PR enzymatic function by binding to the active site of the enzyme (Mitsuya et al., Adv. Pharmacol. 2008, 56, 169-197) preventing proteolytic cleavage events associated with particle maturation. The result is the formation of non-infectious, immature virus particles.
Unfortunately, there are hundreds of mutations of HIV that result in resistance to these drugs. For some, such as the NRTIs like lamivudine, and all available non-nucleoside reverse transcriptase inhibitors (NNRTIs), a single mutation induces high-grade resistance, and for the most part does so in a predictable manner. For others such as zidovudine, abacavir, tenofovir, and most of the protease inhibitors (PIs), high-grade resistance requires the serial accumulation of multiple mutations and is slower to emerge. Others, including didanosine and stavudine also produce low levels of drug resistance in some cases (Adamson et al., Mol. Interv. 2009, 9, 70-74). Thus, the field of HIV research must remain actively engaged in developing new drugs against novel targets.